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(Hypertension. 2005;45:759.)
© 2005 American Heart Association, Inc.

Original Articles

Soluble Epoxide Hydrolase Is a Main Effector of Angiotensin II–Induced Hypertension

Oliver Jung; Ralf P. Brandes; In-Hae Kim; Frank Schweda; Ronald Schmidt; Bruce D. Hammock; Rudi Busse; Ingrid Fleming

From the Institut für Kardiovaskuläre Physiologie and ZAFES (O.J., R.P.B., R.B., I.F.), Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; Department of Entomology and UC Davis Cancer Center (I.-H.K., B.D.H.), University of California, Davis; Institut für Physiologie (F.S.), Universität Regensburg, Germany; and Pharmazentrum Frankfurt (R.S.), Institut für Klinische Pharmakologie and ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, Germany.

Correspondence to Ralf P. Brandes, Institut für Kardiovaskuläre Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail r.brandes{at}em.uni-frankfurt.de

The soluble epoxide hydrolase (sEH) metabolizes vasodilatory epoxyeicosatrienoic acids (EETs) to their di-hydroxy derivatives. We hypothesized that the metabolism of EETs by the sEH contributes to angiotensin II–induced hypertension and tested the effects of a water-soluble sEH inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) on blood pressure. AUDA (130 µg/mL in drinking water) did not affect blood pressure in normotensive animals but markedly lowered it in mice with angiotensin II–induced hypertension (1 mg/kg per day). The effect of AUDA was accompanied by an increase in urinary salt and water excretion. Intravenous application of AUDA (8 mg/kg) acutely lowered blood pressure and heart rate in animals with angiotensin II–induced hypertension but failed to affect blood pressure in animals with phenylephrine-induced hypertension (29 mg/kg per day). AUDA (0.1 µmol/L) selectively lowered vascular resistance in an isolated perfused kidney preparation from angiotensin II–pretreated mice but not from control mice. In the perfused hind limb and in isolated carotid arteries from angiotensin II–treated mice, AUDA was without effect. The -hydroxylase inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide, which attenuates formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid, decreased tone in carotid arteries from angiotensin II–treated but not from control mice. These data demonstrate that the decrease in blood pressure observed after sEH inhibition in angiotensin II–induced hypertension can be attributed to an initial reduction in heart rate followed by pressure diuresis resulting from increased perfusion of the kidney. Direct vasodilatation of resistance arteries in skeletal muscles does not appear to contribute to the antihypertensive effects of sEH inhibition in mice.

Key Words: angiotensin • lipids

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